Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance
Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance
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DOI：
10.1182/blood-2006-10-050260
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发表时间：
2007-07-01
期刊：
影响因子：
20.3
通讯作者：
Cleveland, John L.
中科院分区：
文献类型：
--
作者：
Carew, Jennifer S.;Nawrocki, Steffan T.;Cleveland, John L.
需要新的治疗策略来解决伊马替尼耐药的新问题。组蛋白去乙酰化酶（HDAC）抑制剂辛二酰苯胺异羟肟酸（SAHA）正在评估伊马替尼耐药的慢性粒细胞白血病（CML），并具有多种细胞效应，包括诱导自噬和凋亡。考虑到自噬可能促进癌细胞存活，我们假设破坏自噬将增强SAHA的抗癌活性。在这里，我们报告了破坏自噬途径的药物显著增强了SAHA在CML细胞系和表达野生型和伊马替尼耐药突变型BcrAbl（包括T3151）的原代CML细胞中的抑制作用。该方案对恶性细胞具有选择性，其疗效不会因损害p53功能而降低，p53功能是伊马替尼耐药的另一个因素。通过氯喹处理破坏自噬增强SAHA诱导的超氧化物生成，触发溶酶体蛋白酶组织蛋白酶D的重新定位和显著增加，并降低组织蛋白酶-D底物硫氧还蛋白的表达。最后，组织蛋白酶D的敲低降低了这种组合的效力，证明了其作为这种治疗反应的介体的作用。我们的数据表明，当与HDAC抑制剂联合使用时，破坏自噬的药物是治疗常规治疗失败的伊马替尼难治性患者的一种有前途的新策略。
Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of BcrAbl, including T3151. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy.